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Synthesis Antibacterial and Antifungal Activity of Some Novel 35-Disubstituted-1H-124-triazoles.

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714
Arch. Pharm. Chem. Life Sci. 2008, 341, 714 – 720
Full Paper
Synthesis, Antibacterial and Antifungal Activity of Some Novel
3,5-Disubstituted-1H-1,2,4-triazoles
Shweta Sharma1, Saloni Gangal1, Abdul Rauf1, and Maryam Zahin2
1
2
Department of Chemistry, Aligarh Muslim University, Aligarh, India
Department of Agricultural Microbiology, Aligarh Muslim University, Aligarh, India
A rapid and efficient one-pot condensation reaction of long-chain alkyl and alkenyl acid hydrazides and nitriles was carried out to afford 3,5-disubstituted-1H-1,2,4-triazoles. The compounds
5a – o were screened for in-vitro antibacterial activity against the representative panel of two
Gram-positive and two Gram-negative bacteria. All the synthesized compounds were also tested
for their inhibitory action against five strains of fungi. The various compounds show potent
inhibitory action against test organisms. The compounds 5a – o were characterized on the basis
of elemental analysis and spectral data.
Keywords: 3,5-Disubstituted-1H-1,2,4-triazoles / Long-chain alkyl and alkenyl acid hydrazides / Nitriles /
Received: January 7, 2008; accepted: April 28, 2008
DOI 10.1002/ardp.200800005
Introduction
Heterocycles play an important role in all spheres of life
including pharmaceuticals, natural resources, veterinary, agriculture products, analytical reagents, and dyes
[1]. The development of new approaches for the synthesis
of heterocycles decorated with unique functional groups
forms the basis of an extensive research activity in synthetic organic chemistry. Justification of much of the
chemistry directed to the synthesis of the compounds,
possessing nitrogen at the ring fusion, is due to the application of compounds having interesting biological properties in the field of medicinal chemistry. The 1,2,4-triazole moiety is a structural element in certain anti-asthmatic [2], antiviral (ribavirin) [3], antifungal (flucanoazole) [4], antibacterial [5], hypotonic (triazolam) [6] drugs.
Certain compounds containing 1,2,4-triazole nucleus
have been reported to possess bactericidal [7], antiviral
[8], insecticidal [9], anticancer [10], anti-inflammatory
[11], anticonvulsant [12, 13] properties. Also, some triazole derivatives have been synthesized as plant-growth
regulators [14].
Correspondence: Abdul Rauf, Department of Chemistry, Aligarh Muslim
University, Aligarh 202002, India.
E-mail: abduloafchem@gmail.com
Fax: +91 5712702885
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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Owing to its broad spectrum of biological activity [15 –
21], the 1,2,4-triazole ring system represents an attractive
target to invent new substrates for their synthesis and
production of combinatorial libraries. In several pharmacologically active compounds 3,5-disubstituted-1,2,4-triazoles are found. Recent examples include selective adenosine A2A receptor antagonist [22] and the phosphodiesterase V inhibitor [23]. Previously, 1,2,4-triazoles were synthesized by hydrazides and nitriles either by Pinner reaction and Pellizzari condensation which involve the cyclodehydrative condensation between nitrile and hydrazide. These procedures (Scheme 1; path b – d) are usually
conducted at elevated temperature and involve the activation of nitrile to acylamidrazone intermediate 2 prior
to cyclization. These conventional procedures not only
involve high reaction temperature and long reaction
time but also results in low yields of the product [24 – 26].
Herein, we are reporting a simple and scaleable methodology for the one-pot synthesis of 3,5-disubstituted-1,2,4triazoles.
To the best of our knowledge, 3,5-disubstituted-1H1,2,4-triazoles have not yet been reported from longchain saturated and olefinic carboxylic acids. The present
work is in continuation of our study on the synthesis of
heterocycles from such acids. Tetrazoles, [27, 28] pyrazolines [29], tetrazines [30, 31], spiro [oxathiolane-2,29-dihydrotetrazoles] [32], aziridines [33], and triazines [34] have
Arch. Pharm. Chem. Life Sci. 2008, 341, 714 – 720
3,5-Disubstituted-1H-1,2,4-triazoles
715
Scheme 1. Pathways for synthesis of 3,5-disubstituted-1H1,2,4-triazoles.
Scheme 2. Synthesis of 3,5-disubstituted-1H-1,2,4-triazoles
5a – o.
been previously prepared in our lab. Cyanoethoxy and
morpholine derivatives of hydroxy long-chain acids [35]
and fatty esters [36] showed significant antifungal and
antibacterial activity. In view of the above mentioned
pharmacological applications of 1,2,4-triazoles, we considered undertaking the design and synthesis of hitherto
unknown 1,2,4-triazoles bearing a long alkyl and alkenyl
chain.
let for two hydrogens was observed at d = 2.91 for the
methylene protons, alpha to the triazole ring. The structure of 5g was further supported by its mass spectral studies, which showed a molecular ion peak at m/z 299, consistent with its molecular formula C18H25ON3. The base
peak appears at m/z 160. Detailed spectral of the titled
compounds are given in Experimental.
Results and discussion
Chemistry
The 3,5-disubstituted-1H-1,2,4-triazoles 5a – o were synthesized by the condensation of long-chain saturated and
olefinic carboxylic acid hyrazides 3a – e with nitriles 4 in
presence of a catalytic amount of K2CO3 in n-BuOH
(Scheme 2). The use of a catalytic amount of K2CO3 provided the product in reduced reaction time in appreciable yield as compared to methods reported by earlier
workers. As can been seen from Table 1, the scope of the
reaction using saturated, olefinic (internal and terminal),
and hydroxy acid hydrazides was found to be good. The
yields of 3,5-disubstituted-1H-1,2,4-triazoles did not
depend on the length of chain of the acid hydrazide and
were found to be appreciable. The synthesized compounds were identified on the basis of elemental analysis, IR, 1H-NMR, 13C-NMR, and mass spectra. The 1H-NMR
spectrum of 3-(49-hydroxyphenyl)-5-(dec-9-enyl)-1H-1,2,4triazole 5g showed characteristic signals of d = 10.97 of
the -NH proton and multiplets at d = 7.57 – 7.53 for four
aromatic protons. The methine proton of C-10 showed
signals at d = 5.82. C-11 methylene designated as HE
and Hz displayed two distinct d values when coupled
with the adjacent C-10 methine protons. Thus, the 1H
NMR spectrum showed two doublets of a doublet at d =
5.02 and 4.90 for Hz and HE protons, respectively. A trip-
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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Biological studies
All the newly synthesized compounds were evaluated in
vitro against an assortment of two Gram-positive bacteria
Staphylococcus aureus MSSA 22 and Bacillus subtilis ATCC
6051 and two Gram-negative bacteria Escherichia coli K 12
and Salmonella typhimurium MTCC 98 at a concentration
of 100 lg/mL. Chloramphenicol was used as standard
drug for the comparison of the antibacterial results.
Screening results are summarized in Table 2. The newly
generated compounds 5a – o have exerted significant
inhibitory activity against the growth of the tested bacterial strains. The data pertaining to Table 3 reveal that
5a – o have significant influence on the antibacterial profile of S. typhimurium and S. aureus. The synthesized compounds showed good inhibitory results against B. subtilis
and E. coli. In another set of experiments, the above mentioned compounds 5a – o were also examined for their
antifungal activity. Nystatin was used as standard drug
for the comparison of the antifungal results. The synthesized compounds showed excellent inhibitory results for
C. albicans IOA-109 and good results against Penicillium sp.
(laboratory isolate) and Helminthosporum oryzae (2537 laboratory isolate). All compounds showed moderate activity against Trichoderma. viridae (laboratory isolate) and
Aspergillus niger (laboratory isolate) (Table 3). The data
also revealed that 5a – o has produced the marked
enhancement in the potency of these analogues as antifungal and antibacterial agents.
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S. Sharma et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 714 – 720
Table 1. 3,5-Disubstituted-1H-1,2,4-triazoles 5a – o.
Entry
Starting from
R3
R4
R5
Products
Yield (%)
1
3a, 4a
H
H
5a
89
2
3b, 4a
H
H
5b
85
3
3c, 4a
H
H
5c
82
4
3d, 4a
H
H
5d
82
5
3e, 4a
H
H
5e
80
6
3a, 4b
H
OH
5f
81
7
3b, 4b
H
OH
5g
88
8
3c, 4b
H
OH
5h
85
9
3d, 4b
H
OH
5i
83
10
3e, 4b
H
OH
5j
80
11
3a, 4c
OH
OH
5k
81
12
3b, 4c
OH
OH
5l
80
13
3c, 4c
OH
OH
5m
79
14
3d, 4c
OH
OH
5n
79
15
3e, 4c
OH
OH
5o
78
Conclusion
Experimental
The preparation of 3,5-disubstituted-1H-1,2,4-triazole
derivatives of long-chain alkyl and alkenyl acid hydrazides is a valuable addition to the heterocyclic chemistry.
In conclusion, we have developed a useful procedure for
the synthesis of 3,5-disubstituted-1H-1,2,4-triazole from
fatty acid hydazides which could be scaled up to large
quantities. Further biological evaluation of these derivatives may prove potential usefulness.
Anhydrous conditions were achieved by drying flasks and other
equipments in the oven. Reactions were monitored by TLC on
silica gel G. Silica gel (60 – 80 mesh) was used for column chromatography. All reagents and solvents were generally used as
received from commercial suppliers and when required, solvents were dried and distilled before use. Undec-10-enoic, (Z)octadec-9-enoic, and octadecanoic acids were obtained commercially from Fluka Chemicals (Switzerland). The eluent was a mixture of petroleum ether / ethyl acetate in different proportions
for different compounds and was visualized in an iodine chamber. (9Z, 12R)-12-Hydroxyoctadec-9-enoic (ricinoleic) and (9R,
12Z)-9-hydroxyoctadec-12-enoic (isoricinoleic) acids were isolated from the natural sources, i.e. from Ricinus communis and
Wrightia tinctoria seed oils, respectively. The concentrate of pure
hydroxy acids were obtained by Gunstone's partitioning [37] of
freshly prepared fatty acids and further purified by column
chromatography. 1H-NMR spectra were recorded in CDCl3 on a
We are thankful to the SAIF, Panjab University, Chandigarh,
and the Central Drug Research Institute, Lucknow, for providing spectral data.
The authors have declared no conflict of interest.
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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2008, 341, 714 – 720
3,5-Disubstituted-1H-1,2,4-triazoles
717
Table 2. Antibacterial screening data for 3,5-disubstituted-1H-1,2,4-triazoles 5a – o.
Compound
ECa)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
Chlor amphenicol
Control DMSO
a)
b)
c)
d)
Diameter of zone of inhibition (mm) at 100 lg/mL
Gram-negative
Gram-positive
STb)
BSc)
SAd)
14.6 l 0.61
14.2 l 0.64
13.6 l 0.53
13.2 l 0.53
13.2 l 0.50
16.1 l 0.98
15.9 l 0.36
15.4 l 0.61
13.3 l 0.75
13.1 l 0.65
16.6 l 0.59
16.6 l 0.60
15.9 l 0.65
14.0 l 0.91
14.2 l 0.53
25
–
14.6 l 0.42
15.3 l 0.42
15.6 l 0.53
16.5 l 0.42
16.3 l 0.46
17.1 l 0.23
16.7 l 0.61
16.2 l 0.29
17.1 l 0.42
17.4 l 0.41
18.2 l 0.53
18.5 l 0.31
17.1 l 0.12
16.7 l 0.61
17.2 l 0.35
20
–
19.1 l 0.66
18.2 l 0.51
17.1 l 0.23
16.6 l 0.53
16.5 l 0.50
19.1 l 0.25
18.5 l 0.46
18.1 l 0.31
17.1 l 0.63
16.3 l 0.50
20.3 l 0.42
20.2 l 0.53
19.7 l 0.31
19.4 l 0.40
19.2 l 0.35
24
–
15.4 l 0.51
15.5 l 0.50
16.7 l 0.31
15.8 l 0.60
16.6 l 0.53
16.9 l 0.83
16.9 l 0.34
17.8 l 0.72
18.5 l 0.42
18.4 l 0.53
20.3 l 0.46
20.9 l 0.90
21.3 l 0.64
22.5 l 0.50
22.2 l 0.81
26
–
EC: Escherichia coli.
ST: Salmonella typhimurium.
BS: Bacillus subtilis.
SA: Staphylococcus aureus.
Table 3. Antifungal screening data for 3,5-disubstituted-1H-1,2,4-triazoles 5a – o.
Diameter of zone of inhibition (mm) at 100 lg/mL
Compound
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
Nystatin
Control DMSO
a)
b)
c)
d)
e)
CAa)
HOb)
ANc)
TVd)
PNe)
18.37 l 0.31
18.13 l 0.32
18.3 l 0.55
17.2 l 0.49
17.2 l 0.35
19.03 l 0.44
18.9 l 0.55
18.03 l 0.68
17.6 l 0.38
18.03 l 0.85
18.9 l 0.40
18.2 l 0.43
17.7 l 0.44
18.4 l 0.40
17.9 l 0.57
20
–
12.3 l 0.36
12.5 l 0.50
11.2 l 0.49
10.7 l 0.61
10.8 l 0.71
13.1 l 0.57
13.2 l 0.46
14.0 l 0.47
14.2 l 0.47
14.2 l 0.60
13.6 l 0.40
13.9 l 0.75
13.9 l 0.46
14.1 l 0.60
14.7 l 0.55
18
–
15.0 l 0.25
14.7 l 0.86
15.1 l 0.42
14.4 l 0.40
14.8 l 0.80
15.1 l 0.42
14.8 l 0.91
15.1 l 0.55
15.7 l 0.42
15.5 l 0.50
16.1 l 0.40
16.0 l 0.50
15.7 l 0.80
16.1 l 0.48
16.0 l 0.30
18
–
5.1 l 0.42
5.4 l 0.46
5.6 l 0.60
5.5 l 0.50
5.4 l 0.58
6.5 l 0.50
6.7 l 0.42
6.7 l 0.61
6.8 l 0.50
6.9 l 0.59
8.1 l 0.50
8.2 l 0.43
8.8 l 0.25
8.7 l 0.50
9.2 l 0.62
15
–
12.5 l 0.50
12.7 l 0.61
12.9 l 0.80
13.2 l 0.53
13.2 l 0.50
14.6 l 0.55
14.7 l 0.56
15.2 l 0.43
15.2 l 0.58
15.6 l 0.40
16.0 l 0.30
16.5 l 0.55
17.2 l 0.50
17.0 l 0.36
17.4 l 0.43
20
–
CA: Candida albicans.
HO: Helminthosporum oryza.
AN: Aspergillus niger.
TV: Trichoderma viridae.
PN: Penicillium sp.
Bruker DRX-400 instrument Bruker Bioscience, Billerica, MA,
USA). The chemical shifts (d) were measured relative to TMS as
an internal standard. Coupling constants (J) are expressed in Hz.
Mass spectra were obtained on a Jeol SX-102 (FAB) spectrometer
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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
(JEOL, Tokyo, Japan). IR spectra were obtained on Shimadzu
8201 PC FT-IR using KBr pellet with absorption given in cm – 1
(Shimadzu, Tokyo, Japan).
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S. Sharma et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 714 – 720
Synthesis
General procedure for preparation of 3,5-disubstituted1H-1,2,4-triazoles from fatty acid hydrazides
3-Pheny-5-[(8R, 11Z)-8-Hydroxyheptadec-11-enyl]-1H1,2,4-triazole 5e
The hydrazides 3 of corresponding long-chain acids were prepared as reported earlier [34]. A mixture of nitrile (3 mmol) 4,
acid hydrazide 3a-e (1 mmol), and K2CO3 (0.5 mmol) in n-BuOH
(2 mL) was stirred and refluxed at 1508C for 4 hours. The progress of the reaction was monitored on TLC. After completion of
the reaction, the solvent was removed under reduced pressure
and the compounds were adsorbed on silica gel and purified by
column chromatography. All the compounds 5a – o were
obtained as oily liquids.
IR (KBr): 3387 (N-H), 1594 (C=N), 1124 (C-N) cm – 1; 1H-NMR
(400 MHz, CDCl3) d (ppm): 10.98 (s, 1H, -NH-), 7.69 – 7.65 (m, 2H,
Ar-H), 7.62 – 7.55 (m, 1H, Ar-H), 7.49 – 7.45 (m, 2H, Ar-H), 5.36 (m,
2H, -CH=CH-), 3.88 (m, 1H, CHOH), 3.11 (t, 2H, J = 7.6 Hz, -CH2 a to
ring), 2.42 (m, 1H, CHOH), 2.03 (m, 4H, CH2-CH=CH-CH2), 1.98 (m,
2H, -CH2 b to ring), 1.29 (brs, 18H, chain CH2), 0.88 (dist.t, 3H,
CH3). 13C-NMR (100 MHz, CDCl3) d (ppm): 157.2, 146.8, 134.7,
131.5, 129.5, 127.2, 67.3, 39.1, 34.6, 31.8, 29.1, 28.7, 27.1, 22.5,
14.7. MS, m/z (%): [M + 1]+ 398 (5.8), [M]+ 397 (31.2), 368 (33.2), 326
(13.1), 272 (26.1), 228 (19.9), 214 (100), 172 (30.0).
3-Phenyl-5-heptadecyl-1H-1,2,4-triazole 5a
3-(49-Hydroxyphenyl)-5-heptadecyl-1H-1,2,4-triazole 5f
IR (KBr): 3382 (N-H), 1607 (C=N), 1123 (C-N) cm ; H-NMR
(400 MHz, CDCl3) d (ppm): 10.96 (s, 1H, -NH-), 7.69 – 7.67 (m, 2H,
Ar-H), 7.65 – 7.60 (m, 1H, Ar-H), 7.49 – 7.42 (m, 2H, Ar-H), 2.96 (t, J =
7.6 Hz, 2H, -CH2 a to ring), 2.05 (m, 2H, -CH2 b to ring), 1.72 (brs,
28H, chain CH2), 0.86 (dist. t, 3H, CH3). 13C-NMR (100 MHz, CDCl3)
d (ppm): 159.1, 147.9, 133.8, 129.1, 127.3, 32.1, 30.3, 29.9, 28.6,
23.1, 14.8. MS, m/z (%): [M + 1]+ 384 (10.5), [M]+ 383 (36.11), 354
(25.3), 270 (27.7), 214 (63.8), 186 (16.6), 58 (100).
IR (KBr): 3387 (N-H), 1590 (C=N), 1132 (C-N) cm – 1; 1H-NMR
(400 MHz, CDCl3) d (ppm): 10.97 (s, 1H, -NH-), 7.57 – 7.53 (m, 4H,
Ar-H), 6.95 (Ar-OH), 2.78 (t, 2H, J = 7.6 Hz, -CH2 a to ring), 1.92 (m,
2H, -CH2 b to ring), 1.23 (brs, 28H, chain CH2), 0.88 (dist.t, 3H,
CH3). 13C-NMR (100 MHz, CDCl3) d (ppm): 159.1, 151.8, 148.7,
138.9, 129.7, 117.3, 32.5, 30.7, 22.8, 21.7, 14.5. MS, m/z (%): [M +
1]+ 400 (13.8), [M]+ 399 (41.6), 286 (16.6), 272 (83.3), 258 (16.6) 188
(8.3), 174 (44.4), 160 (100).
3-Phenyl-5-(dec-9-enyl)-1H-1,2,4-triazole 5b
3-(49-Hydroxyphenyl)-5-(dec-9-enyl)-1H-1,2,4-triazole 5g
–1
1
IR (KBr): 3392 (N-H), 1594 (C=N), 1122 (C-N) cm – 1; 1H-NMR
(400 MHz, CDCl3) d (ppm): 10.98 (s, 1H, -NH-), 7.66 – 7.64 (m, 2H,
Ar-H), 7.62 – 7.58 (m, 1H, Ar-H), 7.49 – 7.45 (m, 2H, Ar-H), 5.82 (tdd,
1H, JH 8 CH2 = 6.6 Hz, JH HZ = 10.2 Hz, JH HE = 17.1 Hz, CH2=CH-), 5.02
(dd, 1H, JHZ H = 10.2 Hz, JHz HE = 1.2 Hz, HZ C=CH-), 4.90 (dd, 1H,
JH HE = 17.1 Hz, JHE HZ = 1.2 Hz, HE C=CH-), 3.10 (t, 2H, J = 7.6 Hz,
-CH2 a to ring), 2.05 (m, 2H, CH2-CH=CH2), 1.99 (m, 2H, -CH2 b to
ring), 1.38 (10H, brs, chain CH2). 13C-NMR (100 MHz, CDCl3) d
(ppm): 158.9, 147.2, 139.8, 133.9, 129.6, 127.6, 114.6, 32.8, 30.8,
29.2, 28.3, 22.9, 14.2. MS, m/z (%): [M + 1]+ 284 (14.7), [M]+ 283
(10.8), 270 (28.3), 242 (29.9), 228 (11.8), 214 (18.3), 186 (26.2), 144
(100).
IR (KBr): 3390 (N-H), 1590 (C=N), 1129 (C-N) cm – 1 1H-NMR
(400 MHz, CDCl3) d (ppm): 10.97 (s, 1H, -NH-), 7.57 – 7.53 (m, 4H,
Ar-H), 6.93 (Ar-OH), 5.82 (tdd, 1H, JH 8 CH2 = 6.6 Hz, JH HZ = 10.2 Hz,
JH HE = 17.1 Hz, CH2=CH-), 5.02 (dd, 1H, JHE H = 10.2 Hz, JHE HZ =
1.2 Hz, HZ C=CH-), 4.90 (dd, 1H, JHE H = 17.1 Hz, JHE HZ = 1.2 Hz, HE
C=CH-), 2.91 (t, 2H, J = 7.9 Hz, -CH2 a to ring), 2.02 (m, 2H, -CH2CH=CH2), 1.93 (m, 2H, -CH2 b to ring), 1.38 (brs, 10H, chain CH2).
13
C-NMR (100 MHz, CDCl3) JHE H (ppm): 158.7, 151.2, 148.1, 139.7,
129.1, 116.2, 114.4, 34.2, 33.7, 29.2, 24.7. MS, m/z (%): [M + 1]+ 300
(19.9), [M]+ 299 (12.3), 272 (12.5), 244 (17.3), 230 (3.9), 216 (2.2),
188 (3.9), 174 (4.2), 160 (100).
3-Phenyl-5-(heptadec-8-enyl)-1H-1,2,4-triazole 5c
3-(49-Hydroxyphenyl)-5-(heptadec-8-enyl)-1H-1,2,4triazole 5h
IR (KBr): 3382 (N-H), 1597 (C=N), 1133 (C-N) cm – 1; 1H-NMR
(400 MHz, CDCl3) d (ppm): 10.96 (s,1H, -NH-), 7.67 – 7.63 (m, 2H,
Ar-H), 7.60-7.56 (m, 1H, Ar-H), 7.49 – 7.44 (m, 2H, Ar-H), 5.34 (2H,
m, -CH=CH-), 2.97 (t, 2H, J = 7.6 Hz, -CH2 a to ring), 2.05 (m, 4H,
CH2-CH=CH-CH2), 1.96 (m, 2H, -CH2 b to ring), 1.73 (brs, 20H,
chain CH2), 0.86 (dist.t, 3H, CH3). 13C-NMR (100 MHz, CDCl3) d
(ppm): 158.2, 146.9, 134.1, 131.1, 129.0, 128.1, 33.8, 30.8, 29.9,
28.6, 22.6, 14.6. MS, m/z (%): [M + 1]+ 382 (40.5), [M]+ 381 (30.11),
338 (38.3), 310 (27.7), 268 (63.8), 242 (16.6), 158 (100), 144 (10.9).
IR (KBr): 3387(N-H), 1594 (C=N), 1130 (C-N) cm – 1; 1H-NMR
(400 MHz, CDCl3) d (ppm): 10.97 (s, 1H, -NH-), 7.57 – 7.56 (m, 4H,
Ar-H), 6.93 (Ar-OH), 5.39 (2H, m, -CH=CH-), 2.79 (t, 2H, J = 5.7 Hz,
-CH2 a to ring), 2.02 (m, 4H, -CH2-CH=CH-CH2-), 1.96 (m, 2H, -CH2 b
to ring), 1.23 (brs, 20H, chain CH2), 0.88 (dist.t, 3H, CH3). 13C-NMR
(100 MHz, CDCl3) d (ppm): 157.7, 151.2, 148.7, 130.8, 129.1,
118.4, 34.2, 31.8, 29.6, 29.1, 27.0, 24.7, 22.5, 14.6. MS, m/z (%): [M
+ 1]+ 398 (13.8), [M]+ 397 (41.6), 284 (16.6), 258 (16.6) 188 (8.3), 174
(100), 160 (44.4).
3-Phenyl-5-[(8Z, 11R)-11-hydroxyheptadec-8-enyl]-1H1,2,4-triazole 5d
3-(49-Hydroxyphenyl)-5-[(8Z, 11R)-11-hydroxyheptadec8-enyl]-1H-1,2,4-triazole 5i
IR (KBr): 3386 (N-H), 1590 (C=N), 1119 (C-N) cm – 1; 1H-NMR
(400 MHz, CDCl3) d (ppm): 10.99 (s, 1H, -NH-), 7.66 – 7.64 (m, 2H,
Ar-H), 7.60 – 7.57 (m, 1H, Ar-H), 7.49 – 7.46 (m, 2H, Ar-H), 5.34 (m,
2H, -CH=CH-), 3.88 (m, 1H, CHOH), 3.11 (t, 2H, J = 7.6 Hz, -CH2 a to
ring), 2.43 (m, 1H, CHOH), 2.05 (m, 4H, CH2-CH=CH-CH2), 1.89 (m,
2H, -CH2 b to ring), 1.73 (brs, 18H, chain CH2), 0.89 (dist.t, 3H,
CH3). 13C-NMR (100 MHz, CDCl3) d (ppm): 157.9, 146.8, 134.0,
131.6, 129.2, 127.9, 67.8, 39.2, 34.6, 31.2, 29.4, 28.7, 27.1, 22.7,
14.9. MS, m/z (%): [M + 1]+ 398 (9.8), [M]+ 397 (21.2), 340 (13.2), 312
(13.1), 282 (26.8), 200 (39.9), 186 (100), 172 (30.0).
IR (KBr): 3390 (N-H), 1590 (C=N), 1123 (C-N) cm – 1; 1H-NMR
(400 MHz, CDCl3) ( (ppm): 10.98 (s, 1H, -NH-), 7.58 – 7.52 (m, 4H,
Ar-H), 6.98 (Ar-OH), 5.46 (m, 2H, -CH=CH-), 3.88 (m, 1H, -CH-OH),
3.44 (t, 2H, J = 7.5 Hz, -CH2 a to ring), 2.31 (m, 1H, -CH-OH), 2.04
(m, 4H, -CH2-CH=CH-CH2-), 1.91 (m, 2H, -CH2 b to ring), 1.33 (brs,
18H, chain CH2), 0.86 (dist.t, 3H, CH3). 13C-NMR (100 MHz, CDCl3)
d (ppm): 157.9, 151.6, 148.5, 130.8, 129.3, 118.7, 67.8, 39.2, 34.1,
31.8, 29.6, 28.9, 27.2, 24.7, 22.5, 14.3. MS, m/z (%): [M + 1]+ 414
(12.2), [M]+ 413 (26.13), 370 (75.8), 356 (60.9), 328 (33.4), 202 (69.8),
174 (14.2), 160 (100).
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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com
Arch. Pharm. Chem. Life Sci. 2008, 341, 714 – 720
3-(49-Hydroxyphenyl)-5-[(8R, 11Z)-8-Hydroxyheptadec11-enyl]-1H-1,2,4-triazole 5j
IR (KBr): 3379 (N-H), 1592 (C=N), 1119 (C-N) cm – 1; 1H-NMR
(400 MHz, CDCl3) d (ppm): 10.99 (s, 1H, -NH-), 7.57-7.53 (m, 4H, ArH), 6.93 (Ar-OH), 5.39 (m, 2H, -CH=CH-), 3.88 (m, 1H, -CH-OH), 3.23
(t, 2H, J = 6.4 Hz, -CH2 a to ring), 2.28 (m, 1H, -CH-OH), 2.04 (m, 4H,
-CH2-CH=CH-CH2-), 1.89 (m, 2H, -CH2 b to ring), 1.27 (brs, 18H,
chain CH2), 0.86 (dist.t, 3H, CH3). 13C-NMR (100 MHz, CDCl3) d
(ppm): 158.9, 151.6, 148.7, 131.1, 129.4, 118.6, 67.3, 39.6, 34.1,
31.8, 29.5, 28.7, 27.2, 24.5, 22.1, 14.4. MS, m/z (%): [M + 1]+ 414
(12.5), [M]+ 413 (29.1), 342 (51.2), 316 (33.3), 288 (9.8), 188 (100),
174 (18.8), 160 (80.2).
3-(49,59-Dihydroxyphenyl)-5-(heptadecyl)-1H-1,2,4triazole 5k
IR (KBr): 3349 (N-H), 1604 (C=N), 1134 (C-N) cm – 1; 1H-NMR
(400 MHz, CDCl3) d (ppm): 10.97 (s, 1H, -NH-), 7.16 (d, 1H, J =
1.6 Hz, Ar-H), 7.07 (d, 1H, J = 2 Hz, Ar-H), 7.03 (d, 1H, J = 2 Hz, ArH), 6.89 (Ar-OH), 6.87 (Ar-OH), 2.78 (t, 2H, J = 7.6 Hz, -CH2 a to
ring), 1.92 (m, 2H, -CH2 b to ring), 1.23 (brs, 28H, chain CH2), 0.88
(dist.t, 3H, CH3). 13C-NMR (100 MHz, CDCl3): 164.5, 145.1, 144.2,
121.9, 115.9, 32.1, 30.3, 28.9, 22.3, 14.5. MS, m/z (%): [M + 1]+ 416
(17.0), [M]+ 415 (66.0), 356 (10.4), 314 (2.1), 300 (31.2), 208 (19.2),
190 (12.5), 176 (100).
3-(49,59-Dihydroxyphenyl)-5-(dec-9-enyl)-1H-1,2,4triazole 5l
IR (KBr): 3387 (N-H), 1596 (C=N), 1130 (C-N) cm – 1; 1H-NMR
(400 MHz, CDCl3) d (ppm): 10.98 (s, 1H, -NH-), 7.11 (d, 1H, J =
1.6 Hz, Ar-H), 7.04 (d, 1H, J = 2 Hz, Ar-H), 7.02 (d, 1H, J = 2 Hz, ArH), 6.88 (Ar-OH), 6.87 (Ar-OH), 5.82 (tdd, 1H, JH 8 CH2 = 6.6 Hz,
JH HZ = 10.2 Hz, JH HE = 17.1 Hz, CH2=CH-), 5.02 (dd, 1H, JHZ H =
10.2 Hz, JHZ HE = 1.2 Hz, HZ C=CH-), 4.90 (dd, 1H, JHE H = 17.1 Hz,
JHE HZ = 1.2 Hz, HE C=CH), 3.13 (t, 2H, J = 8 Hz, -CH2 a to ring), 2.02
(m, 2H, -CH2-CH=CH2), 1.93 (m, 2H, -CH2 b to ring), 1.38 (brs, 10H,
chain CH2). 13C-NMR (100 MHz, CDCl3) d (ppm): 164.9, 145.8,
144.8, 139.9, 121.9, 116.7, 114.6, 34.2, 33.7, 29.2, 28.4, 24.2. MS,
m/z (%): [M + 1]+ 316 (25.7), [M]+ 315 (23.8), 288 (44.2), 274 (66.6),
243 (17.1), 208 (36.3), 198 (14.6), 176 (100).
3-(49,59-Dihydroxyphenyl)-5-(heptadec-8-enyl)-1H-1,2,4triazole 5m
IR (KBr): 3384 (N-H), 1594 (C=N), 1127 (C-N) cm – 1; 1H-NMR
(400 MHz, CDCl3) d (ppm): 10.97 (s, 1H, -NH-), 7.11 (d, 1H, J =
1.6 Hz, Ar-H), 7.04 (d, 1H, J = 2 Hz, Ar-H), 7.02 (d, 1H, J = 2 Hz, ArH), 6.93 (Ar-OH), 6.89 (Ar-OH), 5.34 (m, 2H, -CH=CH-), 2.78 (t, 2H, J
= 7.6 Hz, -CH2 a to ring), 2.02 (m, 4H, -CH2-CH=CH-CH2-), 1.92 (m,
2H, -CH2 b to ring), 1.23 (brs, 20H, chain CH2), 0.88 (dist.t, 3H,
CH3). 13C-NMR (100 MHz, CDCl3) d (ppm): 163.4, 146.8, 144.8,
131.9, 121.6, 119.8, 33.1, 29.9, 25.6, 22.7, 14.9. MS, m/z (%): [M +
1]+ 414 (17.0), [M]+ 413 (66.0), 356 (10.4), 314 (12.1), 300 (31.2), 208
(19.2), 190 (100), 176 (57.5).
3-(49,59-Dihydroxyphenyl)-5-[(8Z, 11R)-11hydroxyheptadec-8-enyl]-1H-1,2,4-triazole 5n
IR (KBr): 3386 (N-H), 1597 (C=N), 1123 (C-N) cm – 1; 1H-NMR
(400 MHz, CDCl3) d (ppm): 10.98 (s, 1H, -NH-), 7.13 (d, 1H, J =
1.6 Hz, Ar-H), 7.04 (d, 1H, J = 2 Hz, Ar-H), 7.01 (d, 1H, J = 2 Hz, ArH), 6.89 (Ar-OH), 6.86 (Ar-OH), 5.46 (m, 2H, -CH=CH-), 3.88 (m, 1H,
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2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
3,5-Disubstituted-1H-1,2,4-triazoles
719
-CH-OH), 3.44 (t, 2H, J = 7.5 Hz, -CH2 a to ring), 2.31 (m, 1H, -CHOH), 2.04 (m, 4H, -CH2-CH=CH-CH2-), 1.91 (m, 2H, -CH2 b to ring),
1.33 (brs, 18H, chain CH2), 0.86 (dist.t, 3H, CH3). 13C-NMR
(100 MHz, CDCl3) (ppm): 163.9, 147.8, 145.1, 131.8, 121.1, 119.2,
68.2, 39.8, 37.2, 33.1, 29.9, 27.6, 24.1, 22.7, 14.3. MS, m/z (%): [M +
1]+ 430 (6.6), [M]+ 429 (28.3), 344 (43.3), 260 (13.8), 253 (41.6), 208
(8.3), 190 (47.2), 176 (100).
3-(49,59-Dihydroxyphenyl)-5-[(8R, 11Z)-8hydroxyheptadec-11-enyl]-1H-1,2,4-triazole 5o
IR (KBr): 3392 (N-H), 1600 (C=N), 1123 (C-N) cm – 1; 1H-NMR
(400 MHz, CDCl3) d (ppm): 10.98 (s, 1H, -NH-), 7.11 (d, 1H, J =
1.6 Hz, Ar-H), 7.04 (d, 1H, J = 2 Hz, Ar-H), 7.02 (d, 1H, J = 2 Hz, ArH), 6.89 (Ar-OH), 6.87 (Ar-OH), 5.39 (m, 2H, -CH=CH-), 3.88 (m, 1H,
-CH-OH), 3.23 (t, 2H, J = 6.4 Hz, -CH2 a to ring), 2.28 (m, 1H, J =
7.2 Hz, -CH-OH), 2.04 (m, 4H, -CH2-CH=CH-CH2-), 1.89 (m, 2H, -CH2
b to ring), 1.27 (brs, 18H, chain CH2), 0.86 (dist.t, 3H, CH3). 13CNMR (100 MHz, CDCl3) d (ppm): 163.6, 147.5, 145.1, 131.7, 121.2,
119.6, 68.4, 39.8, 37.4, 33.1, 29.5, 27.3, 24.2, 22.4, 14.2. MS, m/z
(%): [M + 1]+ 430 (55.5), 372 (55.5), [M]+ 429 (8.3), 332 (41.6), 301
(22.2), 280 (13.6), 208 (8.3), 176 (100).
Biological evaluation
Antibacterial activity
The newly synthesized compounds were screened in vitro against
an assortment of two Gram-positive bacteria Staphylococcus aureus MSSA 22 and Bacillus subtilis ATCC 6051 and two Gram-negative bacteria Escherichia coli K12 and Salmonella typhimurium
MTCC 98. Screening results are summarized in Table 2. All the
synthesized compounds were dissolved in DMSO. The antibacterial activity of test compounds and standard chloramphenicol
was done by filter paper disc method [38]. Media with DMSO was
set up as control. All cultures were routinely maintained on NA
(nutrient agar) and incubated at 378C. The inoculums of bacteria
were performed by growing the culture in NA broth at 378C overnight. The culture was centrifuged at 1000 rpm, pellets were
resuspended, and diluted in sterile NSS to obtain viable count
105 CFU/mL. With the help of spreader, 0.1 mL of approximately
diluted bacterial culture suspension was spread on NA plates
uniformly. Sterile 8-mm discs (Hi-media Pvt. Ltd.) were impregnated with 100 lg/mL concentration of the test compounds.
Antibiotic disc, chloramphenicol (30 lg/disc, Hi-Media) was used
as control. The disc was placed onto the plate. Each plate had
one control disc impregnated with solvent. The plates were then
incubated for 24 h at 378C, and the resulting zones of inhibition
(in mm) were measured. Diameters of the zone of inhibition
(mm) were measured and the average diameters for the test samples were calculated in triplicate sets.
Antifungal activity
The standard agar disc diffusion method [38] was performed to
evaluate the antifungal property of the test compounds and
standard nystatin. The newly synthesized compounds were
screened for Aspergillus niger (laboratory isolate), Candida albicans IOA-109, Penicillium sp. (laboratory isolate), Trichoderma viridae (laboratory isolate), Helminthosporum oryzae (2537 ICAR, Jaipur); see Table 3. The synthesized compounds were dissolved in
DMSO. Media with DMSO was set up as control. All cultures were
routinely maintained on SDA and incubated at 288C. Spore formation of filamentous fungi was prepared from seven-day old
culture in sterile normal solution (8% NaCl) and diluted to
www.archpharm.com
720
S. Sharma et al.
obtain approximately 105 CFU/mL. The inoculum of non-sporing
fungi C. albicans was performed by growing the culture in SD
broth at 378C overnight. The culture was centrifuged at
1000 rpm, pellets was resuspended, and diluted in sterile NSS to
obtain a viable count 105 CFU/ml. With the help of spreader,
0.1 mL of the approximately diluted fungal culture suspension
was spread on SDA plates uniformly. Sterile 8-mm discs (Himedia Pvt. Ltd., Mumbai, India) were impregnated with test compounds. Antibiotic disc, nystatin (30 lg/disc Hi-Media) was used
as control. The disc was placed onto the plate. Each plate had
one control disc impregnated with solvent. The plates were incubated at 288C for filamentous fungi for 72 h or more, while for C.
albicans plates were incubated at 378C for 18 – 48 h. Antifungal
activity was determined by measuring the diameters of the
inhibition zone (mm) in triplicate sets.
Arch. Pharm. Chem. Life Sci. 2008, 341, 714 – 720
[16] H. J. Wadsworth, S. M. Jenkins, B. S. Orlek, F. Cassidy, et al.,
J. Med. Chem. 1992, 35, 1280 – 1290.
[17] S. M. Jenkins, H. J. Wadsworth, S. Bromidge, B. S. Orlek, et
al., J. Med. Chem. 1992, 35, 2392 – 2406.
[18] G. Burrell, J. M. Evans, M. S. Hadley, F. Hicks, G. Stemp,
Bioorg. Med. Chem. Lett. 1994, 4, 1285 – 1290.
[19] W. R. Tully, C. R. Gardner, R. J. Gillespie, R. Westwood, J.
Med. Chem. 1991, 34, 2060 – 2067.
[20] S. K. Thompson, A. M. Eppley, J. S. Frazee, M. G. Darcy, et
al., Bioorg. Med. Chem. Lett. 1994, 4, 2441 – 2446.
[21] J. V. Dunica, J. B. Santella, C. A. Higley, M. K. VanAtten, et
al., Bioorg. Med. Chem. Lett. 1998, 8, 775 – 780.
[22] A. Alanine, L. Anselm, L. Steward, S. Thomi, et al., Bioorg.
Med. Chem. Lett. 2004, 14, 817 – 821.
[23] B. Dumaitre, N. Dodic, J. Med. Chem. 1996, 39, 1635 – 1644.
References
[1] J. B. Polya in Comprehensive Heterocyclic Chemistry, (Eds.:
A. R. Katritzky, C. W. Rees, K. T. Potts), Pergamon Press,
Oxford, 1984, Vol. 5, p. 733.
[2] Y. Naito, F. Akahoshi, S. Takeda, T. Okada, et al., J. Med.
Chem. 1996, 39, 3019 – 3029.
[3] E. De Clercq, J. Clin. Virol. 2004, 30, 115 – 133.
[4] X. Collin, A. Sauleau, J. Coulon, Bioorg. Med. Chem. Lett.
2003, 13, 2601 – 2605.
[5] S. Papakonstantinou-Garoufalias, N. Pouli, P. Marakos, A.
Chytyroglou-Ladas, Farmaco. 2002, 57, 973 – 977.
[6] J. B. Hester, A. D. Rudzik, B. V. Kamdar, J. Med. Chem. 1971,
14, 1078 – 1081.
[7] G. Van Reen, J. Heeres, 1979 U. S. Pat. 4160, 838.
[8] O. G. Todoulou, A. E. Papadaki-Valiraki, S. Ikeda, E. De
Clercq, Eur. J. Med. Chem. 1994, 29, 611 – 620.
[9] G. Tanaka, Japan Kokai 1974, 7495, 973, Chem. Abst. 1975,
82, 156320 h.
[10] O. Bekircan, B. Kahveci, M. Kucuk, Turk. J. Chem. 2006, 30,
29 – 40.
[11] M. Tandon, J. P. Barthwal, T. N. Bahalla, K. P. Bhargava, Ind.
J. Chem. 1981, 20B, 1017 – 1018.
[12] M. I. Husain, M. Amir, J. Ind. Chem. Soc. 1986, 63, 317 – 319.
[13] N. Gulerman, S. Rollas, M. Kiraz, A. C. Ekinci, A. Vidin,
Farmaco. 1997, 52, 691 – 695.
[14] E. Raymonds, S. Raymond, G. D. Alan, U.K. Pat. Appl. GB 2,
175, 301: Chem. Abst. 1987, 107, 134310n.
[15] C. Chen, R. Dagnino, C. Q. Huang, J. R. McCarthy, D. E.
Grigoriadis, Bioorg. Med. Chem. Lett. 2001, 11, 3165 – 3168.
i
2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
[24] P. H. Olesen, A. R. Sorensen, B. Urso, P. Kurtzhals, et al., J.
Med. Chem. 2003, 46, 3333 – 3341; H. J. Breslin, T. A. Miskowski, M. J. Kukla, H. J. De Winter, et al., Bioorg. Med. Chem.
Lett. 2003, 13, 4467 – 4471; J. J. Baldwin, P. A. Kasinger, F. C.
Novello, J. M. Spradue, D. E. Duggen, J. Med. Chem. 1975, 18,
895 – 900; J. E. Francis, L. A. Gorczyca, G. C. Mazzenga, H.
Meckler, Tetrahedron Lett. 1987, 28, 5133 – 5136.
[25] H. Weidinger, J. Kranz, DE Patent 1958, 1076136.
[26] Neelima, A. P. Bhaduri, Ind. J. Chem. 1983, 22B, 79 – 80.
[27] J. Mustafa, M. S. Ahmad Jr., A. Rauf, S. M. Osman, J. Am. Oil
Chem. Soc. 1984, 61, 555 – 558.
[28] A. Rauf, H. Parveen, J. Oleo. Sci. 2004, 53, 279 – 283.
[29] R. Agrawal, A. Rauf, M. Ahmad, J. Am. Oil Chem. Soc. 1989,
66, 970 – 971.
[30] M. T. Saeed, J. Mustafa, A. Rauf, S. M. Osman, J. Am. Oil
Chem. Soc. 1992, 69, 481 – 484.
[31] M. T. Saeed, J. Mustafa, A. Rauf, S. M. Osman, J. Am. Oil
Chem. Soc. 1992, 69, 396 – 397.
[32] M. H. Ansari, M. T. Saeed, M. Ahmad, J. Chem. Res. Synop.
1990, 4, 126 – 127.
[33] A. Rauf, S. Ahmad, J. Chem. Res. 2005, 6, 407 – 409.
[34] A. Rauf, S. Sharma, S. Gangal, ARKIVOC, 2007, xvi, 137 –
147.
[35] M. Ahmed, F. Ahmad, S. M. Osman, J. Am. Oil Chem. Soc.
1985, 62, 1578 – 1580.
[36] A. Rauf, H. Parveen, Ind. J. Chem. 2005, 44B, 1273 – 1276.
[37] F. D. Gunstone, J. Chem. Soc. 1954, 1611 – 1616.
[38] A. W. Bauer, W. M. M. Kirby, J. C. Sherris, M. Turck, Am. J.
Clin. Path. 1966, 45, 493 – 496.
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